Cord-blood transplants reborn

Colleen Delaney's methods of increasing cord-blood stem cells may make cord-blood transplants more readily available and successful worldwide

May 19, 2005

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By COLLEEN STEELQUIST

Dr. Colleen Delaney and colleagues in the Bernstein lab have influenced stem-cell growth and differentiation into specialized cell types. By getting cord-blood stem cells to make more of themselves, Delaney hopes to encourage faster engraftment and give patients a better chance of survival.

Photo by Todd McNaught

More than 430,000 babies are born worldwide every day. With each new life comes the potential to save lives, through the blood that remains in the cut umbilical cord and placenta following birth.

Within this blood is a treasure trove of cells that can develop into a new, healthy blood system, with the curative power to banish disease and restore the immune system.

Although it's long been known that cord blood is a potential source of stem cells for transplants to treat leukemia and other blood diseases, the small number of these healing cells in each unit collected has hampered its use. But a new strategy could overcome this limitation — paving the way for many more people to benefit from this lifesaving procedure.

Birthing a cord-blood transplant program at the Hutchinson Center is the aspiration of Dr. Colleen Delaney, a pediatric oncologist and researcher in the Clinical Research Division. Her research holds the promise of increasing the number and success of cord-blood transplants at the Hutchinson Center and worldwide. By using a unique approach pioneered at the Center, Delaney's hope is that under the right laboratory conditions, she can get the stem cells to make more of themselves — thus increasing the number of precious cells from a single donor to a transplant patient.

Stem-cell transplants involve destroying a leukemia patient's cancerous blood system with some combination of radiation and chemotherapy, followed by the infusion of healthy, donated stem cells. The point at which the new blood system forms is called engraftment. The period between infusion and engraftment is very risky for the patient, whose immune system has been destroyed. Increasing the number of stem cells or "dose" is important because research shows that the success of a cord-blood transplant is directly related to the number of stem cells transplanted. Higher doses of stem cells encourage faster engraftment and a better chance of survival. This not only assures higher success rates in general, but it also makes cord-blood transplants available to older children and adults, as larger people require a higher cell dose.

Advantages of cord blood

At present, the Center performs an average of just three cord-blood transplants annually and only in pediatric patients. Cord blood contains only one-tenth the number of stem cells as bone marrow. Because of this low number, engraftment following a cord-blood transplant takes an average of 25 days, compared to about 15 days for a bone-marrow transplant. "Any day longer is worrisome, so it's not really a home run," said Delaney, explaining why these transplants are done infrequently.

"Currently, there's such a low cell dose in a cord-blood graft that the amount of time it takes for those blood cells to form a new blood system in a larger patient is so long that the patient often dies from infectious complications," she said. "I looked at this as an opportunity to say, 'How can we make this better?'"

Cord blood is worthy of such persistence. It has three main advantages over conventional stem-cell sources (bone marrow and circulating blood): it is readily available, fewer viral infections are transmitted with it, and it is immunologically "naïve," which means it does not need to be as stringently matched with the recipient's tissue type. The risk of graft-vs.-host disease, a common post-transplant side effect, is reduced. The easier-to-match feature could be especially beneficial for patients with rare tissue types or mixed ethnicities — many of whom currently die before a donor match is found.

The ability of cord-blood stem cells to differentiate, or change into other types of cells in the body, holds significant promise for improving the treatment of health conditions besides cancer, such as heart disease, spinal-cord injury, stroke and Alzheimer's. However, cord-blood cells are not the same as embryonic stem cells, which have the potential to become life.

A novel approach

Conventional methods for stimulating cord-blood stem cells to multiply have failed. But Delaney and her colleagues in Dr. Irwin Bernstein's lab have pinpointed ways to influence stem cell growth and differentiation into specialized cell types. In 2002, they developed a new method for growing the cells on a protein called Delta, which activates a gene — Notch — that can prevent stem cells from differentiating. Growing cord-blood cells in the presence of the protein boosts the number of stem cells in a cord-blood donation. In their pre-clinical work in mouse models, the researchers achieved a 100- to 200-fold increase in the number of cells grown.

This novel and successful approach has put Fred Hutchinson on the fast track. "No one else has cultured cells in this way," Delaney said. "And others have tried to figure out how to make stem cell stay a stem cell, but most have not been successful so far."

Delaney's plans for increasing the usability of cord blood begin with a joint clinical study with the University of Minnesota. Scheduled to start soon, Delaney and fellow researchers are investigating whether giving patients a "double-unit" cord-blood transplant from two unrelated donors is an effective method for increasing the cell dose. A single unit of cord blood doesn't contain an adequate cell dose for about 60 percent to 70 percent of patients who would benefit from a cord-blood transplant. It is not yet known whether the rate of engraftment, and therefore survival, can be improved with this approach.

A second approach combines the Bernstein lab's earlier research with the double-unit transplant method. The Center's Cell Processing cGMP Facility — which manufactures cell-based products — is currently developing production techniques to allow the Delta-boosted cell preparations to be used in therapeutic trials, which begin next year. In this study, a double-unit transplant will be done, with one of the units expanded in the laboratory to help the patient's blood system engraft faster.

"We think the cells we're growing in the lab will give someone more rapid early engraftment until the true stem cells from the non-expanded unit kick in, creating a two-stage engraftment," Delaney said.

"If this works, the overall long-term goal is to create a shared resource," she said. "We're developing a technology for the world to use."

There have been more than 3,000 cord-blood transplants performed worldwide since the first such transplant in France in 1988. While placentas and umbilical cords are still routinely discarded as "biological waste," 22 public banks have been established in the United States to collect, store and distribute donated cord blood. The Institute of Medicine of the National Academies is advocating for the creation of a national cord-blood coordinating center to increase and manage cord-blood donations. By increasing the size and quality of the cord-blood inventory, government researchers say nearly 90 percent of all patients who need a transplant should be able to find a suitable match from either cord-blood banks or bone-marrow donor registries.

"For those thousands of people who are looking for a bone-marrow match, at least 30 percent can't find one — and that number is much, much higher for minorities," Delaney said. "If we can figure out the cell dose issues, cord-blood transplants will open up a door for all of those patients."